A critical cue for localizing sound is the difference in the time of its arrival at the two ears, which is first analyzed in a brainstem structure called the medial superior olive (MSO). MSO neurons are activated when excitatory inputs from the two ears arrive in coincidence, but they also receive massive inhibitory inputs whose roles in MSO function have not been elucidated. We propose that two distinct groups of inhibitory neurons operate in complementary fashion to limit the duration of the coincidence detection window and preserve sensitivity to interaural temporal differences of MSO neurons. One cell group, which may synchronize its activity to excitatory inputs in order to shorten their duration, is active at low sound levels and uses glycine as its neurotransmitter. The second cell group, which generates asynchronous, tonic hyperpolarization in the MSO cell and thereby requires exact coincidence of excitatory inputs to reach action potential threshold, is active at high sound levels and uses GABA and glycine as its neurotransmitters. Aim 1 will study the structure and termination patterns of these inhibitory circuits. We will test the notion that synchronous inhibition is tonotopic and matched to the pattern of excitatory innervation but that asynchronous inhibition is diffuse and crosses tonotopic axes of the MSO. In Aim 2 we will measure the synchronization of inhibitory neurons to sound through extracellular single unit recordings of their activity. Aims 3 and 4 will test the role of inhibition in coincidence detection and in the representation of simultaneous sound sources in the population of MSO cells. Single unit activity of MSO neurons will be recorded in the absence and presence of iontophoretically applied antagonists of glycinergic and GABAergic neurotransmission. By defining biological mechanisms underlying sound localization, the proposed research will contribute to better strategies for hearing preservation following damage to the auditory system, such as through design or activation of cochlear nucleus prostheses, and for the design of speech recognition systems used in complex acoustic environments